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1.
Nat Neurosci ; 23(3): 386-397, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32066985

RESUMO

Repeat-associated non-AUG-initiated translation of expanded CGG repeats (CGG RAN) from the FMR1 5'-leader produces toxic proteins that contribute to neurodegeneration in fragile X-associated tremor/ataxia syndrome. Here we describe how unexpanded CGG repeats and their translation play conserved roles in regulating fragile X protein (FMRP) synthesis. In neurons, CGG RAN acts as an inhibitory upstream open reading frame to suppress basal FMRP production. Activation of mGluR5 receptors enhances FMRP synthesis. This enhancement requires both the CGG repeat and CGG RAN initiation sites. Using non-cleaving antisense oligonucleotides (ASOs), we selectively blocked CGG RAN. This ASO blockade enhanced endogenous FMRP expression in human neurons. In human and rodent neurons, CGG RAN-blocking ASOs suppressed repeat toxicity and prolonged survival. These findings delineate a native function for CGG repeats and RAN translation in regulating basal and activity-dependent FMRP synthesis, and they demonstrate the therapeutic potential of modulating CGG RAN translation in fragile X-associated disorders.


Assuntos
Expansão das Repetições de DNA/genética , Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/genética , Repetições de Trinucleotídeos/genética , Animais , Linhagem Celular , Sobrevivência Celular/genética , Feminino , Proteína do X Frágil de Retardo Mental/biossíntese , Células-Tronco Pluripotentes Induzidas , Masculino , Camundongos , Neurônios/metabolismo , Oligonucleotídeos Antissenso/farmacologia , Biossíntese de Proteínas , Ratos , Ratos Long-Evans , Ratos Sprague-Dawley , Receptor de Glutamato Metabotrópico 5/biossíntese , Receptor de Glutamato Metabotrópico 5/genética
2.
Brain Nerve ; 71(11): 1190-1208, 2019 Nov.
Artigo em Japonês | MEDLINE | ID: mdl-31722305

RESUMO

In 2011, C9orf72 hexanucleotide (GGGGCC) repeat expansion (HRE) in intron 1 was reported as the most common cause of sporadic and familial amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD) in the Caucasian population. In the Japanese population, the C9orf72 repeat expansion was found to account for 0.2% cases of sporadic ALS and 2.6% of familial ALS. Notably, among individuals in the Kii peninsula which has recorded high incidence of ALS or ALS/PDC (parkinsonism-dementia complex), the frequency of C9orf72 repeat expansion was 20% (3/15) indicating high prevalence. It is important to obtain detailed family history of ALS and FTD to understand the cause of the diseases including the C9orf72 mutation.


Assuntos
Esclerose Amiotrófica Lateral/genética , Proteína C9orf72/genética , Demência Frontotemporal/genética , Expansão das Repetições de DNA , Humanos , Japão , Proteínas
3.
Neurology ; 93(17): e1605-e1617, 2019 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-31578300

RESUMO

OBJECTIVE: To define the natural history of the C9orf72 amyotrophic lateral sclerosis (C9ALS) patient population, develop disease biomarkers, and characterize patient pathologies. METHODS: We prospectively collected clinical and demographic data from 116 symptomatic C9ALS and 12 non-amyotrophic lateral sclerosis (ALS) full expansion carriers across 7 institutions in the United States and the Netherlands. In addition, we collected blood samples for DNA repeat size assessment, CSF samples for biomarker identification, and autopsy samples for dipeptide repeat protein (DPR) size determination. Finally, we collected retrospective clinical data via chart review from 208 individuals with C9ALS and 450 individuals with singleton ALS. RESULTS: The mean age at onset in the symptomatic prospective cohort was 57.9 ± 8.3 years, and median duration of survival after onset was 36.9 months. The monthly change was -1.8 ± 1.7 for ALS Functional Rating Scale-Revised and -1.4% ± 3.24% of predicted for slow vital capacity. In blood DNA, we found that G4C2 repeat size correlates positively with age. In CSF, we observed that concentrations of poly(GP) negatively correlate with DNA expansion size but do not correlate with measures of disease progression. Finally, we found that size of poly(GP) dipeptides in the brain can reach large sizes similar to that of their DNA repeat derivatives. CONCLUSIONS: We present a thorough investigation of C9ALS natural history, providing the basis for C9ALS clinical trial design. We found that clinical features of this genetic subset are less variant than in singleton ALS. In addition, we identified important correlations of C9ALS patient pathologies with clinical and demographic data.


Assuntos
Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/metabolismo , Proteína C9orf72/genética , Idade de Início , Esclerose Amiotrófica Lateral/epidemiologia , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Biomarcadores/urina , Expansão das Repetições de DNA , Feminino , Seguimentos , Heterozigoto , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos Retrospectivos
4.
Neurology ; 93(19): e1748-e1755, 2019 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-31619481

RESUMO

OBJECTIVE: To assess the amount of phosphorylated and nonphosphorylated TAR DNA-binding protein 43 (TDP-43) in the motor brain regions of cases of amyotrophic lateral sclerosis (ALS) with and without repeat expansions in the ATXN2 or C9ORF72 genes. METHODS: The 45-kDa phosphorylated form of TDP-43 and 43-kDa nonphosphorylated form of TDP-43 were quantified by immunoblot in postmortem brain tissue from the motor cortex, spinal cord, and cerebellar vermis of 23 cases with ALS with repeat expansions in the ATXN2 or C9ORF72 genes and sporadic disease and 10 controls. RESULTS: Significantly greater levels of phosphorylated TDP-43 were identified in the motor cortex of cases with ALS with C9ORF72 expansions, and significantly greater amounts of phosphorylated TDP-43 were found in the spinal cord of cases with ALS with intermediate ATXN2 expansions. In contrast, however, similar levels of nonphosphorylated TDP-43 were found in all 3 regions between ALS groups. CONCLUSION: Despite its central role in the pathogenesis of ALS and the emergence of potential targets to modify its aggregation, TDP-43 levels have not been quantified in pathologically confirmed cases with ALS. The present results demonstrating significant differences in phosphorylated but not nonphosphorylated TDP-43 levels suggest that different posttranslational modifications are involved in the generation of greater pathologic TDP-43 levels identified here in our cohort of cases with genetic expansions. These findings are consistent with emerging studies implicating distinct pathomechanisms in the generation of pathologic TDP-43 in cases with ALS with C9ORF72 or ATXN2 expansions and are of relevance to therapeutic research aimed at reducing pathologic TDP-43 in all or a subset of patients with ALS.


Assuntos
Esclerose Amiotrófica Lateral/metabolismo , Ataxina-2/genética , Encéfalo/metabolismo , Proteína C9orf72/genética , Proteínas de Ligação a DNA/metabolismo , Medula Espinal/metabolismo , Idoso , Idoso de 80 Anos ou mais , Esclerose Amiotrófica Lateral/genética , Estudos de Casos e Controles , Vermis Cerebelar/metabolismo , Expansão das Repetições de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Córtex Motor/metabolismo , Fosforilação , Processamento de Proteína Pós-Traducional
6.
Nat Commun ; 10(1): 4920, 2019 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-31664034

RESUMO

Familial Adult Myoclonic Epilepsy (FAME) is characterised by cortical myoclonic tremor usually from the second decade of life and overt myoclonic or generalised tonic-clonic seizures. Four independent loci have been implicated in FAME on chromosomes (chr) 2, 3, 5 and 8. Using whole genome sequencing and repeat primed PCR, we provide evidence that chr2-linked FAME (FAME2) is caused by an expansion of an ATTTC pentamer within the first intron of STARD7. The ATTTC expansions segregate in 158/158 individuals typically affected by FAME from 22 pedigrees including 16 previously reported families recruited worldwide. RNA sequencing from patient derived fibroblasts shows no accumulation of the AUUUU or AUUUC repeat sequences and STARD7 gene expression is not affected. These data, in combination with other genes bearing similar mutations that have been implicated in FAME, suggest ATTTC expansions may cause this disorder, irrespective of the genomic locus involved.


Assuntos
Proteínas de Transporte/genética , Cromossomos Humanos Par 2/genética , Expansão das Repetições de DNA , Epilepsias Mioclônicas/genética , Íntrons , Adolescente , Adulto , Criança , Pré-Escolar , Mapeamento Cromossômico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Adulto Jovem
7.
Nat Commun ; 10(1): 4919, 2019 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-31664039

RESUMO

Familial Adult Myoclonic Epilepsy (FAME) is a genetically heterogeneous disorder characterized by cortical tremor and seizures. Intronic TTTTA/TTTCA repeat expansions in SAMD12 (FAME1) are the main cause of FAME in Asia. Using genome sequencing and repeat-primed PCR, we identify another site of this repeat expansion, in MARCH6 (FAME3) in four European families. Analysis of single DNA molecules with nanopore sequencing and molecular combing show that expansions range from 3.3 to 14 kb on average. However, we observe considerable variability in expansion length and structure, supporting the existence of multiple expansion configurations in blood cells and fibroblasts of the same individual. Moreover, the largest expansions are associated with micro-rearrangements occurring near the expansion in 20% of cells. This study provides further evidence that FAME is caused by intronic TTTTA/TTTCA expansions in distinct genes and reveals that expansions exhibit an unexpectedly high somatic instability that can ultimately result in genomic rearrangements.


Assuntos
Expansão das Repetições de DNA , Epilepsias Mioclônicas/genética , Proteínas de Membrana/genética , Ubiquitina-Proteína Ligases/genética , Adolescente , Adulto , Idoso , Mapeamento Cromossômico , Feminino , Humanos , Íntrons , Masculino , Pessoa de Meia-Idade , Linhagem , Adulto Jovem
8.
Anal Bioanal Chem ; 411(26): 6995-7003, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31435686

RESUMO

DNA repeat expansion sequences cause a myriad of neurological diseases when they expand beyond a critical threshold. Previous electrochemical approaches focused on the detection of trinucleotide repeats (CAG, CGG, and GAA) and relied on labeling of the probe and/or target strands or enzyme-linked assays. However, detection of expanded GC-rich sequences is challenging because they are prone to forming secondary structures such as cruciforms and quadruplexes. Here, we present label-free detection of hexanucleotide GGGGCC repeat sequences, which cause the leading genetic form of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The approach relies on capturing targets by surface-bound oligonucleotide probes with a different number of complementary repeats, which proportionately translates the length of the target strands into charge transfer resistance (RCT) signal measured by electrochemical impedance spectroscopy. The probe carrying three tandem repeats transduces the number of repeats into RCT with a 3× higher calibration sensitivity and detection limit. Chronocoulometric measurements show a decrease in surface density with increasing repeat length, which is opposite of the impedance trend. This implies that the length of the target itself can contribute to amplification of the impedance signal independent of the surface density. Moreover, the probe can distinguish between a control and patient sequences while remaining insensitive to non-specific Huntington's disease (CAG) repeats in the presence of a complementary target. This label-free strategy might be applied to detect the length of other neurodegenerative repeat sequences using short probes with a few complementary repeats. Graphical abstract Short oligomeric probes with multiple complementary repeats detect long neurodegenerative targets with high sensitivity and transduce into higher impedance signal.


Assuntos
Esclerose Amiotrófica Lateral/genética , Expansão das Repetições de DNA , Sondas de Oligonucleotídeos/genética , Sequência de Bases , Técnicas Biossensoriais/métodos , Espectroscopia Dielétrica/métodos , Humanos , Doença de Huntington/genética , RNA/genética
9.
Nat Neurosci ; 22(9): 1383-1388, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31358992

RESUMO

Nucleotide repeat expansions in the C9orf72 gene are the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia. Unconventional translation (RAN translation) of C9orf72 repeats generates dipeptide repeat proteins that can cause neurodegeneration. We performed a genetic screen for regulators of RAN translation and identified small ribosomal protein subunit 25 (RPS25), presenting a potential therapeutic target for C9orf72-related amyotrophic lateral sclerosis and frontotemporal dementia and other neurodegenerative diseases caused by nucleotide repeat expansions.


Assuntos
Proteína C9orf72/genética , Doenças Neurodegenerativas/genética , Proteínas Ribossômicas/genética , Animais , Expansão das Repetições de DNA/genética , Humanos , Biossíntese de Proteínas
10.
Nucleic Acids Res ; 47(15): e90, 2019 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-31194863

RESUMO

Tandem repeat (TR) expansions have been implicated in dozens of genetic diseases, including Huntington's Disease, Fragile X Syndrome, and hereditary ataxias. Furthermore, TRs have recently been implicated in a range of complex traits, including gene expression and cancer risk. While the human genome harbors hundreds of thousands of TRs, analysis of TR expansions has been mainly limited to known pathogenic loci. A major challenge is that expanded repeats are beyond the read length of most next-generation sequencing (NGS) datasets and are not profiled by existing genome-wide tools. We present GangSTR, a novel algorithm for genome-wide genotyping of both short and expanded TRs. GangSTR extracts information from paired-end reads into a unified model to estimate maximum likelihood TR lengths. We validate GangSTR on real and simulated data and show that GangSTR outperforms alternative methods in both accuracy and speed. We apply GangSTR to a deeply sequenced trio to profile the landscape of TR expansions in a healthy family and validate novel expansions using orthogonal technologies. Our analysis reveals that healthy individuals harbor dozens of long TR alleles not captured by current genome-wide methods. GangSTR will likely enable discovery of novel disease-associated variants not currently accessible from NGS.


Assuntos
Expansão das Repetições de DNA , Genoma Humano , Repetições de Microssatélites , Análise de Sequência de DNA/estatística & dados numéricos , Software , Algoritmos , Sequência de Bases , Conjuntos de Dados como Assunto , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Funções Verossimilhança , Alinhamento de Sequência
11.
Cogn Behav Neurol ; 32(2): 120-123, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31205123

RESUMO

Behavioral variant frontotemporal dementia (bvFTD) shares a constellation of clinical features with primary psychiatric disorders. The discovery of new FTD-related genetic mutations has brought attention to this overlap between bvFTD and psychotic disorders. The case reported here raises the question of whether C9orf72 repeat expansion may be involved in neuropsychiatric syndromes beyond the spectrum of neurodegenerative disease. A 61-year-old woman was referred to our memory clinic for behavioral changes and progressive cognitive decline over the last 3 years. Her medical history was significant for schizophrenia since age 36, with an exacerbation of psychotic symptoms at age 55, at which time she slowly worsened, became disorganized and apathetic, and presented new perseverative behaviors. Brain MRI showed mild bilateral frontal and temporal cortical atrophy, and F-fluorodeoxyglucose PET showed bilateral frontal and anterior temporal hypometabolism. Genetic analysis revealed C9orf72 hexanucleotide repeat expansion with more than 80 G4C2 repeats. Recently, FTD due to C9orf72 repeat expansion has been reported to show a high frequency of psychotic presentations. C9orf72 repeat expansion has previously been identified as a rare but possible cause of schizophrenia spectrum disorders. Our case report is characterized by a C9orf72-associated schizophrenia phenotype preceding bvFTD by 2 decades, which might reflect early prodromal neurodegeneration or neurodevelopmental and neurobiological effects of C9orf72 repeat expansion. Analysis of C9orf72 hexanucleotide repeat expansion may be appropriate in patients with schizophrenia spectrum disorders showing new behavioral and/or cognitive changes.


Assuntos
Proteína C9orf72/genética , Expansão das Repetições de DNA/genética , Demência Frontotemporal/genética , Variação Genética/genética , Fenótipo , Esquizofrenia/genética , Feminino , Demência Frontotemporal/diagnóstico por imagem , Humanos , Imagem por Ressonância Magnética/métodos , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons/métodos , Esquizofrenia/diagnóstico por imagem
13.
Nat Neurosci ; 22(6): 863-874, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31110321

RESUMO

An expanded GGGGCC hexanucleotide of more than 30 repeats (termed (G4C2)30+) within C9orf72 is the most prominent mutation in familial frontotemporal degeneration (FTD) and amyotrophic lateral sclerosis (ALS) (termed C9+). Through an unbiased large-scale screen of (G4C2)49-expressing Drosophila we identify the CDC73/PAF1 complex (PAF1C), a transcriptional regulator of RNA polymerase II, as a suppressor of G4C2-associated toxicity when knocked-down. Depletion of PAF1C reduces RNA and GR dipeptide production from (G4C2)30+ transgenes. Notably, in Drosophila, the PAF1C components Paf1 and Leo1 appear to be selective for the transcription of long, toxic repeat expansions, but not shorter, nontoxic expansions. In yeast, PAF1C components regulate the expression of both sense and antisense repeats. PAF1C is upregulated following (G4C2)30+ expression in flies and mice. In humans, PAF1 is also upregulated in C9+-derived cells, and its heterodimer partner, LEO1, binds C9+ repeat chromatin. In C9+ FTD, PAF1 and LEO1 are upregulated and their expression positively correlates with the expression of repeat-containing C9orf72 transcripts. These data indicate that PAF1C activity is an important factor for transcription of the long, toxic repeat in C9+ FTD.


Assuntos
Proteína C9orf72/genética , Expansão das Repetições de DNA/genética , Demência Frontotemporal/genética , Regulação da Expressão Gênica/genética , Proteínas Nucleares/genética , Animais , Drosophila melanogaster , Humanos , Camundongos , Fatores de Transcrição/genética
14.
Nat Neurosci ; 22(6): 851-862, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31086314

RESUMO

The GGGGCC repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, it is not known which dysregulated molecular pathways are primarily responsible for disease initiation or progression. We established an inducible mouse model of poly(GR) toxicity in which (GR)80 gradually accumulates in cortical excitatory neurons. Low-level poly(GR) expression induced FTD/ALS-associated synaptic dysfunction and behavioral abnormalities, as well as age-dependent neuronal cell loss, microgliosis and DNA damage, probably caused in part by early defects in mitochondrial function. Poly(GR) bound preferentially to the mitochondrial complex V component ATP5A1 and enhanced its ubiquitination and degradation, consistent with reduced ATP5A1 protein level in both (GR)80 mouse neurons and patient brains. Moreover, inducing ectopic Atp5a1 expression in poly(GR)-expressing neurons or reducing poly(GR) level in adult mice after disease onset rescued poly(GR)-induced neurotoxicity. Thus, poly(GR)-induced mitochondrial defects are a major driver of disease initiation in C9ORF72-related ALS/FTD.


Assuntos
Esclerose Amiotrófica Lateral/fisiopatologia , Proteína C9orf72/genética , Demência Frontotemporal/fisiopatologia , Mitocôndrias/patologia , ATPases Mitocondriais Próton-Translocadoras/metabolismo , Esclerose Amiotrófica Lateral/genética , Animais , Encéfalo/metabolismo , Expansão das Repetições de DNA , Modelos Animais de Doenças , Demência Frontotemporal/genética , Humanos , Camundongos , Camundongos Transgênicos , Neurônios/metabolismo
15.
Seizure ; 67: 73-77, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30928698

RESUMO

Familial adult myoclonic epilepsy (FAME), also described with different acronyms (ADCME, BAFME, FEME, FCTE and others), is a high-penetrant autosomal dominant condition featuring cortical hand tremors, myoclonic jerks, and occasional/rare convulsive seizures. Prevalence is unknown since this condition is often under-recognized, but it is estimated to be less than 1/35,000. The disease usually starts in the second decade of life and has been genetically associated with at least 4 different loci (8q24, 2p11.1-q12.2, 5p15.31-p15 and 3q26.32-3q28). Recently, the expansion of non coding TTTTA and TTTCA repeats has been identified as the causative mutation in Japanese families linked to the 8q24. The diagnosis is supported by clinical features and electrophysiological investigations as jerk-locked back averaging, C-reflex, and somatosensory-evoked potential. Photic stimulation, emotional stress, and sleep deprivation may trigger both tonic-clonic and myoclonic seizures. FAME has a slow but progressive clinical course occurring with intellectual disability and worsening of both tremor and myoclonus although with a less severe decline compared to other progressive myoclonic epilepsies. Valproate, levetiracetam, and benzodiazepines are considered the first-line treatments.


Assuntos
Expansão das Repetições de DNA , Epilepsias Mioclônicas/genética , Epilepsias Mioclônicas/fisiopatologia , Humanos
16.
Neuron ; 101(6): 1057-1069, 2019 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-30897357

RESUMO

Amyotrophic lateral sclerosis (ALS) is an aggressive neurodegenerative disorder that orchestrates an attack on the motor nervous system that is unrelenting. Recent discoveries into the pathogenic consequences of repeat expansions in C9ORF72, which are the most common genetic cause of ALS, combined with the identification of new genetic mutations are providing novel insight into the underlying mechanism(s) that cause ALS. In particular, the myriad of functions linked to ALS-associated genes have collectively implicated four main pathways in disease pathogenesis, including RNA metabolism and translational biology; protein quality control; cytoskeletal integrity and trafficking; and mitochondrial function and transport. Through the identification of common disease mechanisms on which multiple ALS genes converge, key targets for potential therapeutic intervention are highlighted.


Assuntos
Esclerose Amiotrófica Lateral/genética , Proteína C9orf72/genética , Citoesqueleto/metabolismo , Proteínas de Ligação a DNA/genética , Mitocôndrias/metabolismo , RNA/metabolismo , Superóxido Dismutase-1/genética , Esclerose Amiotrófica Lateral/metabolismo , Grânulos Citoplasmáticos/metabolismo , Expansão das Repetições de DNA , Proteínas de Ligação a DNA/metabolismo , Humanos , Transporte Proteico/genética , Proteínas Serina-Treonina Quinases/genética , Proteína FUS de Ligação a RNA/genética , Estresse Fisiológico , Superóxido Dismutase-1/metabolismo , Fator de Transcrição TFIIIA/genética , Fator de Transcrição TFIIIA/metabolismo , Resposta a Proteínas não Dobradas , Proteína com Valosina/genética
17.
Dement Geriatr Cogn Disord ; 47(1-2): 91-103, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30861516

RESUMO

BACKGROUND/AIMS: The C9ORF72 expansion is known to cause frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). We aim to identify the prevalence of the C9ORF72 expansion in idiopathic normal pressure hydrocephalus (iNPH). METHODS: We analysed the C9ORF72 expansion in a large cohort of patients with possible iNPH (n = 487) and cognitively intact elderly controls (n = 432; age > 65 years). RESULTS: While the C9ORF72 expansion was detected in 1.6% (n = 8/487) of cases with possible iNPH, no control subject was found to carry the mutation. The mean age at onset of symptoms of C9ORF72 expansion carriers was 59 years (range: 52-67 years), 11 years less than non-carriers (p = 0.0002). The most frequent initial/main symptom pertained to gait difficulties. Despite identified mutation, only 3 of the patients fulfilled the criteria for the FTLD-ALS spectrum. Clinically significant shunt response was detected in 6 out of 7 shunted C9ORF72 expansion carriers. CONCLUSION: This is the first study cohort identifying the underlying C9ORF72 expansion in patients with iNPH providing evidence for the potential comorbidity between iNPH and the FTLD-ALS spectrum. Analysis of the C9ORF72 expansion should be considered for patients with probable iNPH presenting with frontal atrophy and personality changes or other severe psychiatric symptoms.


Assuntos
Esclerose Amiotrófica Lateral , Sintomas Comportamentais , Proteína C9orf72/genética , Degeneração Lobar Frontotemporal , Hidrocefalia de Pressão Normal , Idade de Início , Idoso , Esclerose Amiotrófica Lateral/diagnóstico , Esclerose Amiotrófica Lateral/epidemiologia , Esclerose Amiotrófica Lateral/genética , Sintomas Comportamentais/diagnóstico , Sintomas Comportamentais/fisiopatologia , Estudos de Coortes , Correlação de Dados , Expansão das Repetições de DNA , Feminino , Finlândia/epidemiologia , Degeneração Lobar Frontotemporal/diagnóstico , Degeneração Lobar Frontotemporal/epidemiologia , Degeneração Lobar Frontotemporal/genética , Humanos , Hidrocefalia de Pressão Normal/diagnóstico , Hidrocefalia de Pressão Normal/genética , Hidrocefalia de Pressão Normal/psicologia , Masculino , Prevalência
18.
Behav Neurol ; 2019: 2909168, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30774737

RESUMO

Two clinically distinct diseases, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), have recently been classified as two extremes of the FTD/ALS spectrum. The neuropathological correlate of FTD is frontotemporal lobar degeneration (FTLD), characterized by tau-, TDP-43-, and FUS-immunoreactive neuronal inclusions. An earlier discovery that a hexanucleotide repeat expansion mutation in chromosome 9 open reading frame 72 (C9orf72) gene causes ALS and FTD established a special subtype of ALS and FTLD with TDP-43 pathology (C9FTD/ALS). Normal individuals carry 2-10 hexanucleotide GGGGCC repeats in the C9orf72 gene, while more than a few hundred repeats represent a risk for ALS and FTD. The proposed molecular mechanisms by which C9orf72 repeat expansions induce neurodegenerative changes are C9orf72 loss-of-function through haploinsufficiency, RNA toxic gain-of-function, and gain-of-function through the accumulation of toxic dipeptide repeat proteins. However, many more cellular processes are affected by pathological processes in C9FTD/ALS, including nucleocytoplasmic transport, RNA processing, normal function of nucleolus, formation of membraneless organelles, translation, ubiquitin proteasome system, Notch signalling pathway, granule transport, and normal function of TAR DNA-binding protein 43 (TDP-43). Although the exact molecular mechanisms through which C9orf72 repeat expansions account for neurodegeneration have not been elucidated, some potential therapeutics, such as antisense oligonucleotides targeting hexanucleotide GGGGCC repeats in mRNA, were successful in preclinical trials and are awaiting phase 1 clinical trials. In this review, we critically discuss each proposed mechanism and provide insight into the most recent studies aiming to elucidate the molecular underpinnings of C9FTD/ALS.


Assuntos
Esclerose Amiotrófica Lateral/genética , Proteína C9orf72/genética , Expansão das Repetições de DNA/genética , Demência Frontotemporal/genética , Doença de Pick/genética , Animais , Dipeptídeos/genética , Humanos , Doenças Neurodegenerativas/genética
19.
Neurobiol Aging ; 76: 115-124, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30711674

RESUMO

In genetic frontotemporal dementia, cross-sectional studies have identified profiles of presymptomatic neuroanatomical loss for C9orf72 repeat expansion, MAPT, and GRN mutations. In this study, we characterize longitudinal gray matter (GM) and white matter (WM) brain changes in presymptomatic frontotemporal dementia. We included healthy carriers of C9orf72 repeat expansion (n = 12), MAPT (n = 15), GRN (n = 33) mutations, and related noncarriers (n = 53), that underwent magnetic resonance imaging at baseline and 2-year follow-up. We analyzed cross-sectional baseline, follow-up, and longitudinal GM and WM changes using voxel-based morphometry and cortical thickness analysis in SPM and tract-based spatial statistics in FSL. Compared with noncarriers, C9orf72 repeat expansion carriers showed lower GM volume in the cerebellum and insula, and WM differences in the anterior thalamic radiation, at baseline and follow-up. MAPT mutation carriers showed emerging GM temporal lobe changes and longitudinal WM degeneration of the uncinate fasciculus. GRN mutation carriers did not show presymptomatic neurodegeneration. This study shows distinct presymptomatic cross-sectional and longitudinal patterns of GM and WM changes across C9orf72 repeat expansion, MAPT, and GRN mutation carriers compared with noncarriers.


Assuntos
Imagem de Tensor de Difusão , Demência Frontotemporal/diagnóstico por imagem , Demência Frontotemporal/genética , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/patologia , Neuroimagem , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Adulto , Idoso , Proteína C9orf72/genética , Estudos Transversais , Expansão das Repetições de DNA/genética , Feminino , Demência Frontotemporal/patologia , Heterozigoto , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Mutação , Progranulinas/genética , Proteínas tau/genética
20.
PLoS One ; 14(2): e0212198, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30794581

RESUMO

INTRODUCTION: The system of clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated proteins (cas) is a new technology that allows easier manipulation of the genome. Its potential to edit genes opened a new door in treatment development for incurable neurological monogenic diseases (NMGDs). The aim of this systematic review was to summarise the findings on the current development of CRISPR-cas for therapeutic purposes in the most frequent NMGDs and provide critical assessment. METHODS AND DATA ACQUISITION: We searched the MEDLINE and EMBASE databases, looking for original studies on the use of CRISPR-cas to edit pathogenic variants in models of the most frequent NMGDs, until end of 2017. We included all the studies that met the following criteria: 1. Peer-reviewed study report with explicitly described experimental designs; 2. In vitro, ex vivo, or in vivo study using human or other animal biological systems (including cells, tissues, organs, organisms); 3. focusing on CRISPR as the gene-editing method of choice; and 5. featured at least one NMGD. RESULTS: We obtained 404 papers from MEDLINE and 513 from EMBASE. After removing the duplicates, we screened 490 papers by title and abstract and assessed them for eligibility. After reading 50 full-text papers, we finally selected 42 for the review. DISCUSSION: Here we give a systematic summary on the preclinical development of CRISPR-cas for therapeutic purposes in NMGDs. Furthermore, we address the clinical interpretability of the findings, giving a comprehensive overview of the current state of the art. Duchenne's muscular dystrophy (DMD) paves the way forward, with 26 out of 42 studies reporting different strategies on DMD gene editing in different models of the disease. Most of the strategies aimed for permanent exon skipping by deletion with CRISPR-cas. Successful silencing of the mHTT gene with CRISPR-cas led to successful reversal of the neurotoxic effects in the striatum of mouse models of Huntington's disease. Many other strategies have been explored, including epigenetic regulation of gene expression, in cellular and animal models of: myotonic dystrophy, Fraxile X syndrome, ataxias, and other less frequent dystrophies. Still, before even considering the clinical application of CRISPR-cas, three major bottlenecks need to be addressed: efficacy, safety, and delivery of the systems. This requires a collaborative approach in the research community, while having ethical considerations in mind.


Assuntos
Sistemas CRISPR-Cas , Expansão das Repetições de DNA , Edição de Genes/métodos , Técnicas de Transferência de Genes , Doenças Genéticas Inatas , Doenças Neuromusculares , Animais , Modelos Animais de Doenças , Edição de Genes/tendências , Inativação Gênica , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/patologia , Doenças Genéticas Inatas/terapia , Humanos , MEDLINE , Camundongos , Doenças Neuromusculares/genética , Doenças Neuromusculares/patologia , Doenças Neuromusculares/terapia
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